Selective alteration of mitochondrial function by Ditercalinium (NSC 335153), a DNA bisintercalating agent.
The bifunctional intercalator Ditercalinium (NSC 335153) demonstrates an anti-tumoral cytotoxicity markedly different from other intercalating agents. A delayed toxicity is observed in eucaryotic cells, both in vitro and in vivo, at drug concentrations far below those required to observe immediate toxic effects. Fluorescence microscopy demonstrates that Ditercalinium and the mitochondrial-staining fluorophore DiOC2(5) are concentrated in the same cellular organelles of L1210 cells. Electron microscopy of Ditercalinium-treated cells reveals extensive and progressive swelling of mitochondria, with no other ultrastructural changes observed. Ditercalinium uptake and toxicity are in part related to mitochondrial membrane potential. However, drug accumulation itself does not immediately alter the mitochondrial membrane potential. Cellular ATP pool levels and the rate of respiration fall progressively after drug treatment. Nucleotide pools in DC3F cells, measured between drug treatment and death, show marked drops in pyrimidine levels while purine nucleotide levels decline more slowly. Addition of uridine or cytidine partially rescues Ditercalinium-treated cells, while toxicity is increased in the presence of 2-deoxyglucose. The combined evidence indicates that the toxicity of Ditercalinium to murine leukemia cells (L1210) and Chinese Hamster lung cells (DC3F) is due to disruption of mitochondrial function.
Esnault
C
C
Unite de Physiocochimie Macromoleculaire (CNRS UA158, INSERM U140) Institut Gustave Roussy, Villejuif, France.
Brown
S C
SC
Segal-Bendirdjian
E
E
Coulaud
D
D
Mishal
Z
Z
Roques
B P
BP
Le Pecq
J B
JB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D007364:Intercalating Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000502:physiology; D007939:Leukemia L1210 / Q000188:drug therapy; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate; D004247:DNA; D003847:Deoxyglucose; C042804:ditercalinium